Tamoxifen, a nonsteroidal antiestrogen, is available to treat all stages of breast cancer and is being considered as a preventive for breast cancer in high risk women. The drug has been shown to produce a survival advantage in node positive postmenopausal women and to exhibit a low incidence of side effects. The broad application of tamoxifen in the clinic requires not only a clear understanding of the mode of action of antiestrogens but also an understanding of drug resistance. The goal of this proposal is to understand the structural requirements for estrogen and antiestrogen regulated growth of breast cancer cells in culture. Our study of structure activity relationships of novel nonsteroidal compounds will be completed to provide tools to compare and contrast the changes in growth factor (transforming growth factors alpha, beta1, beta2, beta3) growth factor receptor (epidermal growth factor) and steroid hormone receptors (estrogen and progesterone) in MCF-7 and T47D breast cancer cells during replication. New pure antiestrogens (e.g., ICI164,384) may provide a new dimension for the treatment of breast cancer. However, we are naive about the effects that complete estrogen withdrawal will have on the tumor. We have developed several estrogen non-responsive varieties of breast cancer cells (MCF-7 and T47D) by long-term estrogen deprivation. One clone of T47D cells (C4) is of particular interest as it is refractory to estrogens and antiestrogens and appears to have lost the mechanism for both estrogen and progesterone receptor induction. Our aim is to understand receptor and growth factor regulation in antiestrogen resistant breast cancer cells so that novel treatment strategies can be developed to treat patients when antiestrogen resistance occurs in the clinic.